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https://www.readbyqxmd.com/read/27925676/population-pharmacokinetics-and-exposure-response-relationship-of-carfilzomib-in-patients-with-multiple-myeloma
#1
Ying Ou, Sameer Doshi, Anh Nguyen, Fredrik Jonsson, Sanjay Aggarwal, Kanya Rajangam, Meletios A Dimopoulos, A Keith Stewart, Ashraf Badros, Kyriakos P Papadopoulos, David Siegel, Sundar Jagannath, Ravi Vij, Ruben Niesvizky, Richard Graham, Jenn Visich
A population pharmacokinetic (PK) model and exposure-response (E-R) analysis was developed using data collected from 5 phase 1b/2 and 2 phase 3 studies in subjects with multiple myeloma. Subjects receiving intravenous infusion on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) in each cycle at doses ranging from 15 to 20/56 mg/m(2) (20 mg/m(2) in cycle 1 and, if tolerated, escalated to 56 mg/m(2) on day 8 of cycle 1). The population PK analysis indicated that among all the covariates tested, the only statistically significant covariate was body surface area on carfilzomib clearance; however, this covariate was unlikely to be clinically significant...
December 7, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27925651/model-based-dose-selection-for-intravaginal-ring-formulations-releasing-anastrozole-and-levonorgestrel-intended-for-the-treatment-of-endometriosis-symptoms
#2
Isabel Reinecke, Marcus-Hillert Schultze-Mosgau, Rüdiger Nave, Heinz Schmitz, Bart A Ploeger
Pharmacokinetics (PK) of anastrozole (ATZ) and levonorgestrel (LNG) released from an intravaginal ring (IVR) intended to treat endometriosis symptoms were characterized, and the exposure-response relationship focusing on the development of large ovarian follicle-like structures was investigated by modeling and simulation to support dose selection for further studies. A population PK analysis and simulations were performed for ATZ and LNG based on clinical phase 1 study data from 66 healthy women. A PK/PD model was developed to predict the probability of a maximum follicle size ≥30 mm and the potential contribution of ATZ beside the known LNG effects...
December 7, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27922734/population-pharmacokinetics-of-ceritinib-in-adult-patients-with-tumors-characterized-by-genetic-abnormalities-in-anaplastic-lymphoma-kinase
#3
Ying Hong, Vanessa Q Passos, Pai-Hsi Huang, Yvonne Y Lau
Ceritinib is a second-generation selective and potent oral anaplastic lymphoma kinase (ALK) inhibitor approved for ALK-positive advanced non-small cell lung cancer previously treated with crizotinib. Population pharmacokinetic (PK) analysis was performed to describe the PK of ceritinib and was used to evaluate the covariate effects on systemic exposure at its label dose (750 mg orally once daily). Ceritinib concentration-time data from 4 clinical studies were described by a 1-compartment model with delayed first-order absorption and time-dependent elimination...
December 6, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27914982/nanotopography-controls-cell-cycle-changes-involved-with-skeletal-stem-cell-self-renewal-and-multipotency
#4
Louisa C Y Lee, Nikolaj Gadegaard, María C de Andrés, Lesley-Anne Turner, Karl V Burgess, Stephen J Yarwood, Julia Wells, Manuel Salmeron-Sanchez, Dominic Meek, Richard O C Oreffo, Matthew J Dalby
In culture isolated bone marrow mesenchymal stem cells (more precisely termed skeletal stem cells, SSCs) spontaneously differentiate into fibroblasts, preventing the growth of large numbers of multipotent SSCs for use in regenerative medicine. However, the mechanisms that regulate the expansion of SSCs, while maintaining multipotency and preventing fibroblastic differentiation are poorly understood. Major hurdles to understanding how the maintenance of SSCs is regulated are (a) SSCs isolated from bone marrow are heterogeneous populations with different proliferative characteristics and (b) a lack of tools to investigate SSC number expansion and multipotency...
November 24, 2016: Biomaterials
https://www.readbyqxmd.com/read/27909740/clinical-pharmacokinetics-of-magnesium-sulfate-in-the-treatment-of-children-with-severe-acute-asthma
#5
Joseph E Rower, Xiaoxi Liu, Tian Yu, Michael Mundorff, Catherine M T Sherwin, Michael D Johnson
PURPOSE: Intravenous (IV) magnesium sulfate (MgSO4) is used as adjunct therapy to treat acute asthma exacerbations. Despite its clinical use, there is a limited understanding of the disposition of magnesium in children. METHODS: To explore the pharmacokinetics (PK) of IV MgSO4 in this population, we collected retrospective data from 54 children who received IV MgSO4 for treatment of an acute asthma exacerbation at Primary Children's Hospital in Salt Lake City, UT...
December 2, 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27904098/relationship-between-pk-pd-of-cefepime-and-clinical-outcome-in-febrile-neutropenic-patients-with-normal-renal-function
#6
Yoshiko Yamashita, Hidekazu Kamiyama, Asuka Yamamoto, Hiroki Kanoh, Yoshimitsu Yuhki, Akira Ueda, Yukari Kawamoto, Yoshikazu Gotoh, Satoshi Yamamoto
 The efficacy of cefepime (CFPM) is known to depend on the ratio of the time that the serum levels exceed the minimum inhibitory concentration (MIC) to the dosing interval (%T>MIC). The objective of this study was to clarify the relation between %T>MIC and clinical outcome of CFPM, and to identify the optimal dosage regimen. We investigated the outcome of CFPM treatment for febrile neutropenia (FN) patients with normal renal function. Treatment success was defined as the completion of FN therapy with CFPM only...
2016: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/27898568/whole-exome-sequencing-to-identify-novel-biological-pathways-associated-with-infertility-after-pelvic-inflammatory-disease
#7
Brandie D Taylor, Xiaojing Zheng, Toni Darville, Wujuan Zhong, Kranti Konganti, Olayinka Abiodun-Ojo, Roberta B Ness, Catherine M O'Connell, Catherine L Haggerty
BACKGROUND: Ideal management of sexually transmitted infections (STI) may require risk markers for pathology or vaccine development. Previously, we identified common genetic variants associated with chlamydial pelvic inflammatory disease (PID) and reduced fecundity. As this explains only a proportion of the long-term morbidity risk, we used whole-exome sequencing to identify biological pathways that may be associated with STI-related infertility. METHODS: We obtained stored DNA from 43 non-Hispanic black women with PID from the PID Evaluation and Clinical Health Study...
November 28, 2016: Sexually Transmitted Diseases
https://www.readbyqxmd.com/read/27891230/development-of-a-population-pharmacokinetic-model-of-prucalopride-in-children-with-functional-constipation
#8
Erno van Schaick, Marc A Benninga, Amy Levine, Mats Magnusson, Steven Troy
A recent phase 3 trial of prucalopride in children with functional constipation (SPD555-303 ClinicalTrials.gov Identifier: NCT01330381) reported negative efficacy results. Here, we developed a population pharmacokinetic (PK) model of prucalopride in children to assess prucalopride exposure in SPD555-303. An initial population PK model in children was developed based on sampled single-dose data from a phase 1 study (PRU-USA-12). This model was subsequently updated with sampled data from SPD555-303 and used to simulate plasma concentration-time profiles for children aged 6 months to 18 years who were treated once daily with prucalopride 0...
August 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/27890875/induction-of-apoptosis-by-ethanol-extract-of-evodia-rutaecarpa-in-hela-human-cervical-cancer-cells-via-activation-of-amp-activated-protein-kinase
#9
Seon Young Park, Cheol Park, Shin-Hyung Park, Su-Hyun Hong, Gi-Young Kim, Sang Hoon Hong, Yung-Hyun Choi
The fruit of Evodia rutaecarpa (Juss.) Benth has been used widely in traditional medicine therapy. Although it has been shown to possess many pharmacological activities, the molecular mechanisms of its anti-cancer activity have not been clearly elucidated. In the present study, we investigated the pro-apoptotic effects of an ethanol extract isolated from immature fruits of E. rutaecarpa (EEER) in HeLa human cervical cancer cells. EEER treatment decreased the cell viability of HeLa cells in a concentration-dependent manner, which was related to apoptotic cell death resulting from apoptotic body formation, DNA fragmentation, and an increased population of annexin V(+)-positive cells...
November 27, 2016: Bioscience Trends
https://www.readbyqxmd.com/read/27884734/nitric-oxide-coupled-signaling-in-odor-elicited-molecular-events-in-the-olfactory-center-of-the-terrestrial-snail-helix-pomatia
#10
Zoltán Serfőző, Kálmán Nacsa, Zoltán Veréb, Izabella Battonyai, Csaba Hegedűs, Csilla Balogh, Károly Elekes
Olfaction, a chemosensory modality, plays a pivotal role in the orientation and behavior of invertebrates. The central olfactory processing unit in terrestrial stylomatophoran snails is the procerebrum, which contains NO synthesizing interneurons, whose oscillatory currents are believed to be the base of odor evoked memory formation. Nevertheless, in this model the up- and downstream events of molecular cascades that trigger and follow NO release, respectively, have not been studied. Immunocytochemistry and flow cytometry studies performed on procerebral neural perikarya isolated from the snail Helix pomatia revealed cell populations with discrete DAF-2 fluorescence, indicating the release of different amounts of NO...
November 21, 2016: Cellular Signalling
https://www.readbyqxmd.com/read/27884704/enhanced-aggressiveness-of-bystander-cells-in-an-anti-tumor-photodynamic-therapy-model-role-of-nitric-oxide-produced-by-targeted-cells
#11
Jerzy Bazak, Jonathan M Fahey, Katarzyna Wawak, Witold Korytowski, Albert W Girotti
The bystander effects of anti-cancer ionizing radiation have been widely studied, but far less is known about such effects in the case of non-ionizing photodynamic therapy (PDT). In the present study, we tested the hypothesis that photodynamically-stressed prostate cancer PC3 cells can elicit nitric oxide (NO)-mediated pro-growth/migration responses in non-stressed bystander cells. A novel approach was used whereby both cell populations existed on a culture dish, but made no physical contact with one other...
November 22, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27882944/grk6-regulates-ros-response-and-maintains-hematopoietic-stem-cell-self-renewal
#12
Qiumin Le, Wenqing Yao, Yuejun Chen, Biao Yan, Cao Liu, Man Yuan, Yuqing Zhou, Lan Ma
G protein-coupled receptor kinases (GRKs) are critically involved in immune response through regulation of cytokine receptors in mature leukocytes, but their role in hematopoiesis is largely unknown. Here, we demonstrate that GRK6 knockout (GRK6(-/-)) mice exhibit lymphocytopenia, loss of the hematopoietic stem cell (HSC) and multiple progenitor populations. GRK6 deficiency leads to compromised lymphoid differentiation, largely owing to the impairment of HSC self-renewal. Transcriptome and proteomic analysis suggest that GRK6 is involved in reactive oxygen species signaling...
November 24, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27881782/consolidation-of-goal-directed-action-depends-on-mapk-erk-signaling-in-rodent-prelimbic-cortex
#13
Genevra Hart, Bernard W Balleine
: The prelimbic prefrontal cortex (PL) has consistently been found to be necessary for the acquisition of goal-directed actions in rodents. Nevertheless, the specific cellular processes underlying this learning remain unknown. We assessed changes in learning-related expression of mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK1/2) phosphorylation (pERK) in layers 2-3 and 5-6 of the anterior and posterior PL and in the population of neurons projecting to posterior dorsomedial striatum (pDMS), also implicated in goal-directed learning...
November 23, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27880726/chrysophanic-acid-reduces-testosterone-induced-benign-prostatic-hyperplasia-in-rats-by-suppressing-5%C3%AE-reductase-and-extracellular-signal-regulated-kinase
#14
Dong-Hyun Youn, Jinbong Park, Hye-Lin Kim, Yunu Jung, JongWook Kang, Mi-Young Jeong, Gautam Sethi, Kwang Seok Ahn, Jae-Young Um
Benign prostatic hyperplasia (BPH) is one of the most common chronic diseases in male population, of which incidence increases gradually with age. In this study, we investigated the effect of chrysophanic acid (CA) on BPH. BPH was induced by a 4-week injection of testosterone propionate (TP). Four weeks of further injection with vehicle, TP, TP + CA, TP + finasteride was carried on. In the CA treatment group, the prostate weight was reduced and the TP-induced histological changes were restored as the normal control group...
November 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/27875488/esomeprazole-fda-approval-in-children-with-gerd-exposure-matching-and-exposure-response
#15
Justin C Earp, Nitin Mehrotra, Kristina E Peters, Robert P Fiorentino, Donna Griebel, Sue Chih Lee, Andrew Mulberg, Kerstin Röhss, Marie Sandström, Amy Taylor, Christoffer W Tornøe, Erica L Wynn, Jan-Stefan Van der Walt, Christine Garnett
OBJECTIVES: FDA approval of proton-pump inhibitors for infantile GERD has been limited by intra-patient variability in the clinical assessment of GERD. For children 1-17 years old, extrapolating efficacy from adults for IV esomeprazole was accepted. The oral formulation was previously approved in children. Exposure-response and exposure matching analyses were sought to identify approvable pediatric doses. METHODS: Intragastric pH biomarker comparisons between children and adults were conducted...
November 19, 2016: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/27866917/prkag3-polymorphisms-associated-with-sporadic-wolff-parkinson-white-syndrome-among-a-taiwanese-population
#16
Ken-Pen Weng, Yeong-Seng Yuh, Shih-Hui Huang, Hsiang-Chiang Hsiao, Huang-Wei Wu, Jen-Hung Chien, Bo-Hau Chen, Shih-Ming Huang, Kuang-Jen Chien, Luo-Ping Ger
BACKGROUND: The aim of this study was to investigate whether mutation in AMP-activated protein kinase (AMPK) subunit genes (PRKAG3-230) is associated with sporadic, isolated Wolff-Parkinson-White (WPW) syndrome. METHODS: This study consisted of 87 patients with symptomatic WPW syndrome and 93 healthy controls. PRKAG3-230 genotypes were determined using real-time polymerase chain reaction assay. Genotype and allele frequencies of PRKAG3-230 between patients with WPW syndrome and healthy controls were ascertained using chi-square test or Fisher exact test when appropriate...
November 17, 2016: Journal of the Chinese Medical Association: JCMA
https://www.readbyqxmd.com/read/27865929/g2-m-cell-cycle-arrest-on-ht-29-cancer-cells-and-toxicity-assessment-of-triphenylphosphanegold-i-carbonimidothioates-ph3pau-sc-or-nph-r-me-et-and-ipr-during-zebrafish-development
#17
Kah Kooi Ooi, Chien Ing Yeo, Theventhiran Mahandaran, Kok Pian Ang, Abdah Md Akim, Yoke-Kqueen Cheah, Hoi-Ling Seng, Edward R T Tiekink
Phosphanegold(I) thiolates, Ph3PAu[SC(OR)=NPh], R=Me (1), Et (2) and iPr (3), were previously shown to be significantly cytotoxic toward HT-29 cancer cells and to induce cell death by both intrinsic and extrinsic apoptotic pathways whereby 1 activated the p73 gene, and each of 2 and 3 activated p53; 2 also caused apoptotic cell death via the c-Jun N-terminal kinase/mitogen-activated protein kinase pathway. Apoptosis pathways have been further evaluated by mitochondrial cytochrome c measurements and annexin V screening, confirming apoptotic pathways of cell death...
November 4, 2016: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/27863186/model-based-characterization-of-the-pharmacokinetics-of-pembrolizumab-a-humanized-anti-pd-1-monoclonal-antibody-in-advanced-solid-tumors
#18
M Ahamadi, T Freshwater, M Prohn, C H Li, D P de Alwis, R de Greef, J Elassaiss-Schaap, A Kondic, J A Stone
Pembrolizumab, a potent antibody against programmed death 1 (PD-1) receptor, has shown robust antitumor activity and manageable safety in patients with advanced solid tumors. Its pharmacokinetic (PK) properties were analyzed with population PK modeling using pooled data from the KEYNOTE-001, -002, and -006 studies of patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other solid tumor types. Pembrolizumab clearance was low and the volume of distribution small, as is typical for therapeutic antibodies...
November 14, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27863168/integrated-two-analyte-population-pharmacokinetic-model-for-antibody-drug-conjugates-in-patients-implications-for-reducing-pharmacokinetic-sampling
#19
D Lu, L Gibiansky, P Agarwal, R C Dere, C Li, Y-W Chu, J Hirata, A Joshi, J Y Jin, S Girish
An integrated pharmacokinetics (PK) model that simultaneously describes concentrations of total antibody (Tab) and antibody-conjugated monomethyl auristatin E (acMMAE) following administration of monomethyl auristatin E (MMAE)-containing antibody-drug conjugates (ADCs) was developed based on phase I PK data with extensive sampling for two ADCs. Two linear two-compartment models that shared all parameters were used to describe the PK of Tab and acMMAE, except that the deconjugation rate was an additional clearance pathway included in the acMMAE PK model compared to Tab...
November 10, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27853996/a-phase-1-study-combining-the-her3-antibody-seribantumab-mm-121-and-cetuximab-with-and-without-irinotecan
#20
James M Cleary, Autumn J McRee, Geoffrey I Shapiro, Sara M Tolaney, Bert H O'Neil, Jeffrey D Kearns, Sara Mathews, Rachel Nering, Gavin MacBeath, Akos Czibere, Sunil Sharma, W Michael Korn
Background HER3/EGFR heterodimers have been implicated as a mode of resistance to EGFR-directed therapies. Methods This Phase 1 trial assessed the tolerability, maximum tolerated dose (MTD) and pharmacokinetic (PK) properties of the HER-3 antibody seribantumab in combination with cetuximab (Part I) or cetuximab and irinotecan (Part II) in patients with EGFR-dependent cancers. In Part I, escalating doses of seribantumab and cetuximab were administered. In Part II of the trial, escalating doses of seribantumab/cetuximab were combined with irinotecan 180 mg/m2 administered every two weeks...
November 16, 2016: Investigational New Drugs
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